Transplantation

Trained immunity in transplantation

Research topic

Transplantation is a life-enhancing therapeutic option for tens of thousands of patients with end-stage organ failure. While outstanding short-term outcomes have been achieved by pharmacologic immunosuppression, the detrimental effects life-long continuous immunosuppression compromise long-term allograft survival. Novel therapeutic approaches that target the adaptive immune response have been developed, but the long-term transplant outcomes remain suboptimal. This underlines that additional levels of immune regulation must be targeted to develop tolerance-inducing protocols.

Recent data demonstrates that macrophages initiate transplant rejection. In line with these observations, our laboratory has recently discovered that trained immunity represents a previously unrecognized pathway that mediates organ rejection. We hypothesize that failure to induce long-term allograft survival may be due, in part, to the lack of therapeutic protocols that target myeloid cells in vivo and prevent trained immunity. Therefore, the development of an immunotherapy that targets the epigenetic regulation of trained macrophages represents a promising approach to facilitate long-term allograft survival.

Using experimental murine models of organ transplantation, we are focusing on molecular pathways that trigger trained immunity in graft-infiltrating macrophages. We are interested in reprogramming trained macrophages towards regulatory macrophages through the negative regulation of the mammalian target of rapamycin (mTOR). More recently, our laboratory is evaluating the possible role of trained immunity during graft versus host disease (GvHD) after bone marrow transplantation. Overall, our research proposes to characterize the strength and duration of trained immunity in transplant recipients to design novel approaches that target myeloid cells in vivo and significantly advance towards improving the clinical treatment of transplant patients.